Mice with a targeted disruption in the estrogen receptor (ER) gene are being used to learn if estrogen action through the ER is required for development and function of the male reproductive system. Although the male reproductive system was anatomically normal in estrogen receptor knockout (ERKO) mice, they were infertile. The accessory reproductive organ weights and serum LH and FSH levels did not differ significantly between ERKO and wild-type male mice. However, the testosterone levels were elevated, the numbers and percent of sperm that are motile were reduced, testis weights were less, and matings were less frequent in ERKO males than in wild-type males. There were no obvious histological differences between testes of ERKO and wild-type males at 10 days after birth, but the lumen of the seminiferous tubules in ERKO mice became dilated by 20 days. There was subsequently degeneration of the seminiferous tubules in ERKO mice, beginning at the caudal pole of the testis 70-90 days after birth, with degenerating occurring last in tubules at the cranial pole at 6-8 months of age. The most likely cause of the dilation and subsequent degeneration is reduced fluid reabsorption by the efferent ducts that connect the testis to the epididymis. About 85% of the fluid leaving the testis is reabsorbed there by a sodium pump mechanism and these tubules contain higher levels of ER than other male reproductive tract tissues in wild-type mice. Studies were also carried out on the motility of sperm from the cauda epididymis of 8-16 week old ERKO and wild-type mice and their ability to fertilize eggs in vitro. The sperm from ERKO males at all ages were less motile and unable to fertilize eggs in vitro, indicated that infertility was due to altered sperm function, in addition to reduced sperm numbers and mating frequency.